Certain bisphosphonic acids, for example methylene bisphosphonic acid, dichloromethylene bisphosphonic acid, (1-hydroxyethylidene)bisphosphonic acid, (2-aminoethylidene)bisphosphonic acid, (3-amino-1-hydroxypropylidene)bisphosphonic acid and (4-amino-1-hydroxybutylidene)bisphosphonic acid have utility in the treatment of diseases characterized by abnormal calcium metabolism, in particular, diseases involving bone resorption, especially osteoporosis, Paget's disease, malignant hypercalcemia, and metastatic bone disease.
There is a long-felt need to improve the pharmacological properties of bisphosphonic acids. An important disadvantage of bisphosphonic acids in pharmaceutical applications is that they can cause tissue damage, localized pain and irritation following intramuscular or subcutaneous injection. Another disadvantage is that the level of bisphosphonic acid in the blood after intravenous injection reaches a peak within a couple of hours and levels off to less than 10% of the peak value within 5 hours after intravenous injection. As a result, many bisphosphonic acids are taken up in significant quantity by the liver or excreted by the kidneys. When administered orally, bisphosphonic acids suffer from the problem of low bioavailability and, in addition, may exhibit gastrointestinal side effects, particularly with the large oral doses required to provide therapeutic efficacy. The pharmacological profile of bisphosphonic acids is therefore not as favorable as one might desire.
U.S. Pat. No. 4,621,077, issued Nov. 4, 1986, to Rosini and Staibano discloses pharmaceutical compositions comprising (4-amino-1-hydroxybutylidene)-1,1-bisphosphonic acid (ABP) or a water-soluble (sodium, aniline or lysine) salt thereof. The insoluble, calcium salts of ABP are not disclosed.
U.S. Pat. No. 4,446,052, issued May 1, 1984, to Sunberg and Benedict discloses a gel comprising di[(3-amino-1-hydroxypropylidene)-1,1-bisphosphonic acid] tricalcium salt in water. The gel is disclosed to be useful for the treatment of certain disorders of calcium metabolism in warm blooded animals. No suggestion is made that the pharmaceutical compositions containing insoluble salts can be modified to avoid undesirable properties, such as gel formation, caking, particle size growth, relatively high viscosity or poor syringability. It is important to note that a gel formulation suffers severe difficulties in S.C. or I.M. administration and is to be avoided. The suspensions of the present invention overcome such problems inherent with gel formulations.
Three insoluble calcium salts of (4-amino-1-hydroxybutylidene)-1,1-bisphosphonic acid (ABP) wherein the molar ratio of ABP to calcium is 1:1, 2:1, or approximately 3:4 (hereinafter referred to as (ABP)Ca, (ABP).sub.2 Ca, and (ABP).sub.3 Ca.sub.4, respectively) as suspensions in an aqueous pharmaceutical composition at a pH from about 6 to about 7.5 each have pharmaceutical properties very similar to the soluble sodium salts of ABP, but with a much lower propensity to cause tissue damage, pain and irritation following intramuscular or subcutaneous injection. Moreover, the pharmaceutical compositions of the present invention comprising (ABP)Ca, (ABP).sub.2 Ca, or (ABP).sub.3 Ca.sub.4 have very good physical stability (as indicated by lack of caking or gelling of the suspension). The systemic release of ABP from the calcium salts is slow which results in a lower uptake of ABP by the liver as compared to the sodium salts. This slow systemic release results in the desired concentration of ABP in solution and provides benefits in a number of therapeutic uses of ABP including the treatment and prevention of diseases involving bone resorption, especially osteoporosis, Paget's disease, malignant hypercalcemia, and metastatic bone disease.
It is therefore a purpose of this invention to provide an aqueous suspension of insoluble calcium salts of ABP. It is a further purpose of this invention to provide a pharmaceutical compositions comprising an aqueous suspension of an insoluble calcium salt of ABP wherein the molar ratio of ABP to calcium is 1:1, 2:1, or approximately 3:4. It is a further purpose of this invention to provide methods of treatment of calcium disorders virtually without side effects of tissue damage, pain and irritation following intramuscular or subcutaneous injection. Finally, this invention provides methods for the treatment of calcium disorders which require a slow systemic release of ABP.